Antibody-based therapy for cancer treatment offers new hope and treatment options to patients. Based on the current success of several antibodies in treating cancer, monoclonal antibodies represent the fastest growing segment of the biopharmaceutical market. This application proposes to develop a novel small modular immunopharmaceutical (SMIP) approach to cancer therapy that is directed at Fc receptors for IgE. Of the several antibodies and antibody-based therapies that have been approved for marketing, all the antibodies belong to the classical IgG subtype. The mechanism by which many of these antibodies produce efficacy is not known. This application proposes to develop a novel small modular immunopharmaceutical (SMIP) that is directed at Fc receptors for IgE, SMIPs uses these receptors to recruit highly potent effector cells to attach and eliminate cancer cells. Trubion Pharmaceuticals, Inc. will engineer and develop SMIPs directed to CD20, a target already proven tobe vulnerable in the treatment of B cell lymphoma. Trubion will use engineered SMIPs as a path to morepotent biological agents that specifically target and kill cancer cells by cellular mediated mechanisms. Development of these synthetic SMIPs leverage the remarkable specificity, high affinity, and potency of IgE receptors. The engineering aspect of this application concerns remodeling IgE Fc-tailed SMIPs to better achieve improved potency, specificity, and selectivity for use as anticancer agents. The biology aspect concerns adapting highly potent cellular mechanisms of IgE action to eliminate cancer cells while avoiding the toxicity that could be associated with IgE Fc receptor activation. The overall goal of this application is to (i) demonstrate the ability of an engineered anti-CD20 SMIP to specifically treat lymphoma and (ii) establish the general usefulness of IgE Fc-tailed SMIP therapy. Synthetic IgE-based derivatives specific for human CD20will be cloned, expressed, and purified. After passing various biophysical tests for purity and specificity, SMIPs will be tested in vitro for various ADCC activities and evaluated in a cancer model in wildtype mice for their ability to inhibit and eliminate the growth of lymphomas that express CD20 on their surface.